Joe Tsien's research into how animals learn and organize memories caught our attention. Curious to know more, BioTechniques contacted him to find out about the creativity, character, and motivation that led to his success.

One day during my sophomore year in college, I walked into a lab where my professor was recording neural activity in anesthetized rabbits. The whole room was dark except one tiny light shining on the electrode inserted in the brain. It felt so mysterious. When I asked my professor what he was doing, he replied, “Shh, the brain is talking.” That was the moment I heard the spikes popping from the amplifier, and I became hooked on neuroscience.

What has been your most significant contribution to the field so far?

Early in my career, I developed a Cre-loxP technology for creating brain region specific and cell type specific conditional knockout mice. When I first proposed the idea, many colleagues told me it wasn't worth pursuing because Cre-loxP recombination depends on cell replication and brain neurons are all post-mitotic. But it worked, and now the technology serves as a crucial platform for optogenetics, where channelrhodopsin is expressed in specific cells.

When did you begin studying learning and memory?

Using the Cre-loxP technology, we knocked out the NMDA receptor in the mouse hippocampus and found profoundly impaired memory in these mice. At the time, we knew that the NMDA receptor required both voltage and ligand for activation. The NR2A and NR2B subunits were voltage dependent, with NR2B opening the channel for 10-20 ms longer than NR2A. My naïve idea was that if more calcium was coming in, there would be a better chance to learn and form a stronger synapse.

We also knew when and where the NMDA subunits were expressed during development. NR2B was highly expressed in the in younger brain, but later became restricted and reduced in the forebrain to the cortex and hippocampus where learning and memory take place. With maturity, it is largely replaced by NR2A. When I came to the US for graduate school at age 26, it was hard for me to learn English. But some of my friends came here with children who quickly learned to speak perfect American English without any accent. I thought that the transition from NR2B early in development to NR2A at maturity might account for this difference in learning and memory capacity.

“I like to step away from what everybody else is doing and look at questions…that may be more central to revealing the mysteries of the brain.”

I decided to overexpress NR2B, hoping that the juvenile form of the receptor would provide greater plasticity such that the mouse would learn faster and remember longer. Several of my colleagues told me I was crazy to pursue these experiments since evolution had optimized the brain, and there was no way to improve it. When we published our findings that overexpression of NR2B enhanced learning and memory, many of my colleagues didn't believe the results at first, but now the approach is considered obvious and logical.

What are you currently working on?

In 2007, we launched a brain decoding project, which is similar to the brain activity map President Obama recently announced. For the first time, we have been able to describe what memory is and identify how it is organized in the hippocampus at the network level. Initially, we developed a technique to simultaneously record the activity of 200–300 hippocampal neurons in freely behaving mice. Researchers studying electrophysiology in the hippocampus usually monitor place cells, which fire to let animals know their location. We began looking at place cells like everyone else, but it was not exciting for me because place cells have been studied for more than 40 years. Then one day I was looking at a mouse with a cable coming from his head and a lot of neurons displayed on the computer monitor, and I wondered what these neurons were actually doing. I am not a very patient person, so I rocked the bucket to scare the mouse. The computer screen filled with activity and I realized this was telling me something about how we remember dramatic experiences. This led us to develop a set of unconventional behavioral tests for studying episodic memory and ultimately to discover how information is recorded and memory is organized by the hippocampal cell assemblies.

What motivates you to pursue such unconventional experiments?

I like to step away from what everybody else is doing and look at questions that might sound naïve or crazy, but may be more central to revealing the mysteries of the brain. When I developed the Cre-loxP system, I was actually doing my second postdoctoral fellowship. If that project hadn't gone well, I wouldn't have gotten a job. But when I think something might work, I'm willing to follow my intuition, invest my time, and sometimes even risk my career.